Heparins are potent inhibitors of ectonucleotide pyrophosphatase/phospho-diesterase-1 (NPP1) - a promising target for the immunotherapy of cancer.

Introduction: Heparins, naturally occurring glycosaminoglycans, are widely used for thrombosis prevention. Upon application as anticoagulants in cancer patients, heparins were found to possess additional antitumor activities. Ectonucleotidases have recently been proposed as novel targets for cancer immunotherapy. Methods and results: In the present study, we discovered that heparin and its derivatives act as potent, selective, allosteric inhibitors of the poorly investigated ectonucleotidase NPP1 (nucleotide pyrophosphatase/phosphodiesterase-1, CD203a). Structure-activity relationships indicated that NPP1 inhibition could be separated from the compounds' antithrombotic effect. Moreover, unfractionated heparin (UFH) and different low molecular weight heparins (LMWHs) inhibited extracellular adenosine production by the NPP1-expressing glioma cell line U87 at therapeutically relevant concentrations. As a consequence, heparins inhibited the ability of U87 cell supernatants to induce CD4+ T cell differentiation into immunosuppressive Treg cells. Discussion: NPP1 inhibition likely contributes to the anti-cancer effects of heparins, and their specific optimization may lead to improved therapeutics for the immunotherapy of cancer.

Sulfated Polysaccharides from Macroalgae Are Potent Dual Inhibitors of Human ATP-Hydrolyzing Ectonucleotidases NPP1 and CD39.

Extracellular ATP mediates proinflammatory and antiproliferative effects via activation of P2 nucleotide receptors. In contrast, its metabolite, the nucleoside adenosine, is strongly immunosuppressive and enhances tumor proliferation and metastasis. The conversion of ATP to adenosine is catalyzed by ectonucleotidases, which are expressed on immune cells and typically upregulated on tumor cells. In the present study, we identified sulfopolysaccharides from brown and red sea algae to act as potent dual inhibitors of the main ATP-hydrolyzing ectoenzymes, ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) and ecto-nucleoside triphosphate diphosphohydrolase-1 (NTPDase1, CD39), showing nano- to picomolar potency and displaying a non-competitive mechanism of inhibition. We showed that one of the sulfopolysaccharides tested as a representative example reduced adenosine formation at the surface of the human glioblastoma cell line U87 in a concentration-dependent manner. These natural products represent the most potent inhibitors of extracellular ATP hydrolysis known to date and have potential as novel therapeutics for the immunotherapy of cancer.

Probing the solar corona with very long baseline interferometry.

Understanding and monitoring the solar corona and solar wind is important for many applications like telecommunications or geomagnetic studies. Coronal electron density models have been derived by various techniques over the last 45 years, principally by analysing the effect of the corona on spacecraft tracking. Here we show that recent observational data from very long baseline interferometry (VLBI), a radio technique crucial for astrophysics and geodesy, could be used to develop electron density models of the Sun's corona. The VLBI results agree well with previous models from spacecraft measurements. They also show that the simple spherical electron density model is violated by regional density variations and that on average the electron density in active regions is about three times that of low-density regions. Unlike spacecraft tracking, a VLBI campaign would be possible on a regular basis and would provide highly resolved spatial-temporal samplings over a complete solar cycle.

Field demonstration of mode-division multiplexing upgrade scenarios on commercial networks.

We demonstrate three possible scenarios for upgrading current single-mode transmission networks with high capacity few-mode fiber technology using mode-division multiplexing (MDM). The results were obtained from measurements over a number of field-deployed single-mode fiber links with an additional experimental in-line amplified few-mode fiber link. The results confirm the viability of employing MDM using few-mode fiber technology to gradually replace legacy optical systems.

Calcitonin- and katacalcin-like immunoreactivity in human seminal plasma.

iCT was determined in 74 patients by direct RIA. A highly significant increase (371 pg/ml) compared with normal serum concentration (100 pg/ml) was observed. There was no correlation between iCT concentration and ejaculate parameters. In addition monomeric bioactive CT and from the same RNA derived KT were determined from a seminal plasma pool gathered from 25 patients. The measured amounts were similar to those found in plasma. Monomeric CT or KT is not responsible for high amounts of iCT in seminal plasma found by direct radioimmunoassay. High amounts of iCT or iKT are due to two heterogenous peptides with greater molecular mass but have no influence on fertility.

Determination of circulating monomeric katacalcin and calcitonin: physiological studies in normal subjects.

Katacalcin is a recently discovered peptide, contained within the calcitonin precursor. For the highly sensitive radioimmunological measurement of katacalcin and calcitonin we used extraction on C-18, thereby lowering the detection limits in serum to 0.8 pmol/l (katacalcin) and 0.7 pmol/l (calcitonin), and simultaneously improving the specificities of both assays for the monomeric forms of the peptides. Extraction recoveries were greater than 96% and greater than 95% for pure monoiodinated [125I]Tyr(0)-katacalcin and [125I]calcitonin, respectively; and 95-98% and 91-97% respectively for the corresponding unlabelled peptides. This method is sufficiently sensitive and specific for studies on the physiology of both peptides. Gel filtration of serum from a patient with medullary carcinoma of the thyroid showed that the majority of high molecular weight forms of katacalcin and calcitonin did not bind to C-18, and that the eluted material consisted to more than 90% of monomeric katacalcin and calcitonin. Basal levels (mean +/- SEM) of katacalcin were higher in men (3.0 +/- 0.6 pmol/l, age less than 40 years, and 1.8 +/- 0.4 pmol/l, age greater than 40 years) and younger women (2.1 +/- 0.4 pmol/l) than in older women (1.3 +/- 0.6 pmol/l; p less than 0.02). The respective values for calcitonin were 5.1 +/- 0.9 and 4.0 +/- 0.6 pmol/l for young and older men, and 2.3 +/- 0.4 and 2.8 +/- 0.8 pmol/l for young and older women, with a significant sex-related difference in both age groups. Basal serum levels of katacalcin and calcitonin were highly correlated (katacalcin = 0.66 calcitonin -0.12 pmol/l; p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced hepatic fatty-acid synthesis and lowered plasma triacylglycerol (TG) in potassium deficient rats.

Potassium deficiency was induced in rats by feeding a potassium- free synthetic diet containing 5% Resonium A. Feeding this diet for 1 week resulted in a decrease of plasma potassium by about 50% vs. pair fed controls. In hypokalemic rats hepatic fatty-acid synthesis and TG secretion by the liver were significantly reduced. In contrast the removal of an intravenous lipid load occurred optimally under this condition. As a consequence plasma TG levels were reduced in potassium-deficient rats.

Triacylglycerol secretion and fatty acid synthesis by the liver in acute uremic rats.

In bilaterally nephrectomized rats fatty acid synthesis (incorporation of 3H from 3H2O into fatty acids by the liver) and triacylglycerol (TG) secretion by the liver (Triton method) were investigated 24 h after surgery. Starved and fed rats were employed. In uremic rats fatty acid synthesis occurs at a normal rate; prevention of acidosis during uremia by bicarbonate treatment has no influence on lipid synthesis. Following intravenous injections of Triton WR 1339 the TG plasma levels are considerably lower in uremic rats than in corresponding controls. As the plasma volume is significantly higher in uremic animals, there is only an insignificant decrease in the absolute TG secretion rate in these animals. The removal of TG from the blood to the tissues in severely reduced in uremia with acidosis. The normal rates of fatty acid synthesis and nearly normal rates of TG secretion may, therefore, be considered as permissive factors for the development of uremic hypertriglyceridemia. The lesser degree of hypertriglyceridemia in uremia without acidosis is only caused by the better removal of TG from the blood (as could be demonstrated earlier). Fatty acid synthesis and TG secretion do not play any role in this case.

Quantitative modelling and prediction of development times of the free-living stages of Ostertagia ostertagi under controlled and field conditions.

The development of the free-living stages of Ostertagia ostertagi incubated at constant temperatures from 5 to 27 degrees C and in dung pats in the field was observed. The death rates were adequately described by a single exponential functional and the distribution of times for development by a delayed gamma density function. The times of appearance of selected development stages such as maximum numbers of embryonated eggs and half the maximum number of infective larvae, were highly dependent on temperature. The relationships between these times and temperature were adequately described by the Arrhenius equation. The parameters of this equation and mean hourly temperature recorded in dung pats in the field were used to predict development times in the field. A comparison of predicted and observed times showed that an initial delay accounted for a large proportion of the time required for development in dung pats, particularly the embryonation of eggs. This delay was attributed to lack of aeration associated with high moisture content of the dung pat.

Neurophysiological and behavioural changes during mental work in children with Down's syndrome.

Telemetered EEG and ECG were recorded from 18 Down's syndrome children (5;6--11 years) during rest, a visuomotor and a cognitive test, exploration and play. Simultaneously the behaviour was observed and recorded. In comparison with normal children (3;9--5;5 y. resp. 5;6--7;6 y.) the Down's syndrome children showed a low degree of motor activity, reduced attention and exploration and little variation of heart rate in relation to test difficulty. The main findings in the EEG (parieto-occipital recording) were a low amount and a small variability of alpha waves and a high amount of beta waves. This EEG phenomenon which is obviously not due to high activation is discussed with regard to possible connections with defective neurophysiological mechanisms of attention.

A condition for the extinction of a branching process with an absorbing lower barrier.

A branching process with an absorbing lower barrier is considered. This is a Galton-Watson process with the condition that at any generation the number of individuals is greater than a lower barrier or it is equal to zero (i.e. all individuals in populations which are too small die and have no offspring). A necessary and sufficient condition is given for the process to become extinct with probability one. At the end of the paper there are three illustrating examples.